A subject of the present invention is a process for the preparation of optionally substituted p-hydroxymandelic compounds and derivatives.
In the disclosure of the invention which follows, the term, xe2x80x9coptionally substituted p-hydroxymandelic compoundsxe2x80x9d is used to refer to an aromatic compound which carries at least one xe2x80x94CHOHxe2x80x94COOH group in para position of a hydroxyl group.
The present invention relates, more particularly, to the preparation of p-hydroxymandelic acid and 3-methoxy p-hydroxymandelic acid.
One of the conventional synthesis routes for p-hydroxymandelic acids consists in carrying out the condensation, in alkaline medium, of glyoxylic acid on phenol and/or its corresponding derivatives.
The yield is limited by the fact that the condensation reaction is not selective and also produces o-hydroxymandelic acids and dimandelic acids.
Furthermore, the reaction yield is reduced due to a parasitic secondary reaction. In fact, glyoxylic acid in aqueous alkaline medium is converted according to Caniizaro""s reaction into oxalic and glycolic acids.
In order to prevent this Cannizaro""s reaction from becoming dominant and destroying the glyoxylic acid, a proposal has been made in FR-A 2 132 364 for the condensation reaction to be carried out in a dilute aqueous medium and at low temperature or ambient temperature.
In view of the difficulty in obtaining satisfactory reaction yields, it is important to control the various parameters of the process, and, in particular, the quality of the glyoxylic acid used.
The most worthwhile process from an industrial viewpoint for the preparation of glyoxylic acid consists in oxidising the glyoxal with nitric acid. In this way, aqueous solutions of glyoxylic acid are obtained, which, in addition to unreacted glyoxal, also contain oxalic acid, organic acids, such as formic acid, acetic acid, glycolic acid, and nitric acid.
Until now, new methods have been constantly sought for the separation and purification of glyoxylic acid.
Therefore, a process was proposed in DE-A 1 198 339 which first and foremostly permitted the nitric acid to be eliminated, followed by the oxalic acid using basic ion exchange resins, followed by the glyoxal and the other impurities by over-concentration of the solution and crystallisation.
In DE-A 2 501 743, a process was disclosed in which the glyoxylic acid is separated from these impurities by extraction using aliphatic or cycloaliphatic alcohols, or aliphatic esters of alcohols with low carbon condensation.
A process for obtaining aqueous solutions of glyoxylic acid free from other acids has also been described in FR-A 2 552 426 which consists in treating the starting solution with an organic nitrogenous compound, preferably a tertiary amine, at a temperature which is at the most equal to 50xc2x0 C., then in extracting the glyoxylic acid by extraction of the organic phase with water, at a higher temperature.
A constant concern has therefore been noted in the prior art of providing a solution of glyoxylic acid which is free of impurities.
Running counter to this teaching, it has been found that within the scope of preparing optionally substituted p-hydroxymandelic compounds condensation of glyoxylic acid and of the corresponding phenol is carried out with an increased yield, provided that said reaction is carried out in the presence of a dicarboxylic acid used in a certain quantity.
A precise subject of the present invention is a process for the preparation of optionally substituted p-hydroxymandelic compounds and derivatives, which consists in carrying out the condensation, in water, in the presence of an alkaline agent, of an aromatic compound with at least one hydroxyl group and the para position of which is free, with glyoxylic acid, said process being characterised in that the reaction is carried out in the presence of an effective quantity of a catalyst compound with at least two carboxylic functions.
In accordance with the process of the invention, the use of a catalyst according to the invention allows the reaction yield to be increased.
Another advantage of the process according to the invention is that it can involve a more technical glyoxylic acid containing, inter alia, oxalic acid.
The process according to the invention is used, most particularly, with phenol but also with substituted phenols which have at least one non-substituted para position.
The aromatic nucleus has at least one hydroxyl group, but it can also have one or more other substituents. Generally, xe2x80x9cseveral substituentsxe2x80x9d means less than four substituents per aromatic nucleus.
Any substituent can be present provided that it is does not interfere in the reaction of the invention.
Therefore, the process according to the invention is well suited for use with hydroxylated aromatic compounds corresponding to the following formula (I): 
in which formula (I):
the para position is free,
x is an integer between 1 and 4,
R represents:
a hydrogen atom,
a hydrocarbon group having from 1 to 20 carbon atoms selected from the alkyl, alkoxy, hydroxyalkyl, cycloalkyl, aryl, phenoxy, alkoxyalkyl, fluoroalkyl, hydroxyalkoxyalkylene groups,
a hydroxyl group,
a xe2x80x94CHO group,
an acyl group having from 2 to 6 carbon atoms,
a halogen atom, preferably a fluorine, chlorine or bromine atom,
two R groups placed on two vicinal carbon atoms can form together with the carbon atoms to which they are attached, a benzene ring.
Examples of R radicals which can be attached to the aromatic nucleus are given hereinafter:
alkyl radicals, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-octyl, 2-ethyl hexyl, decyl, octadecyl, eicosly,
alkoxy radicals, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, hexyloxy, decyloxy, hexadecylocy, octadecylocy, or a phenoxy radical,
hydroxyalkyl radicals, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyhexyl, hydroxydecyl,
cycloalkyl radicals, such as cylcopentyl, cyclohexyl, cycloheptyl,
fluoroalkyl radicals, such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1,1-trifluoro ethyl, pentafluoroethyl, fluoropropyl, fluorobutyl, tribluoroamyl,
hydroxyalkyoxyalkylene radicals, such as hydroxymethyloxyethylene, hydroxyethyl di-(oxyethylene), hydroxyethyl tri-(oxyethylene), 1,2-hydroxyethyloxypropylene, hydroxyethyloxybutylene, hydroxypropyloxypropylene, hydroxybutyloxybutylene, hydroxybutyl di-(oxybutylene),
halogen atoms, such as fluorine, chlorine, bromine, or iodine.
Quite preferably, hydroxylated aromatic compounds are used in the process of the invention, corresponding to the general formula (I), in which:
x is equal to 0, 1,2 or 3,
R represents one of the following groups or functions:
a hydrogen atom,
a linear or branched alkyl radical having from 1 to 10 carbon atoms, and preferably from 1 to 4 carbon atoms,
a linear or branched alkoxy radical having from 1 to 10 carbon atoms, preferably from 1 to 4 carbon atoms,
anxe2x80x94OH group,
a xe2x80x94CHO group,
a halogen atom,
a xe2x80x94CF3 group.
Still more preferably, the compounds of formula (I) are selected in which the R radicals which are identical or different are a hydrogen atom, a linear or branched alkyl radical with 1 to 4 carbon atoms, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl radicals, a linear or branched alkoxy radical having 1 to 4 carbon atoms, such as the methoxy or ethoxy radicals, a xe2x80x94CHO group, or a chlorine atom, and x is preferably equal to 0 or 1.
By way of illustration of compounds corresponding to formula (I), the following can be mentioned:
those corresponding to formula (I) in which x is equal to 0, such as phenol,
those corresponding to formula (I) in which x is equal to 1, such as
pyrocatechin
resorcin
o-cresol
m-cresol
2-ethyl phenol
3-ethyl phenol
2-propyl phenol
2-sec-butyl phenol
2-tert-butyl phenol
3-tert-butyl phenol
2-methoxy phenol (guaiacol)
3-methoxy-phenol
2-ethoxy phenol (guetol)
2-isopropoxy phenol
salicylic aldehyde
methyl salicylate
2-chloro phenol
3-chloro phenol
3-nitro phenol
those corresponding to formula (I) in which x is equal to 2, such as:
2,3-dimethyl phenol
2,5-dimethyl phenol
3,5-dimethyl phenol
2-hydroxy 5-acetamido benzaldehyde
2-hydroxy 5-ethamido benzaldehyde
2,3-dichloro phenol
2,5-dichloro phenol
3.5-dichloro phenol
pyrogallol
those corresponding to formula (I) in which x is equal to 3, such as:
2,3,5-trimethyl phenol
3,5-di-tert butyl phenol
2,3,5-trichloro phenol
those corresponding to formula (I) having a naphthalenic radical, such as:
1-naphthol
2-naphthol
1,2-dihydroxy naphthalene
1,5-dihydroxy naphthalene
2,3-dihydroxy naphthalene
2,6-dihydroxy naphthalene
2,7-dihydroxy naphthalene
6-bromo 2-naphthol
those corresponding to formula (I) having a chain formation of benzene nuclei:
2-phenoxy phenol
3-phenoxy phenol
Of the list of afore-mentioned compounds, the aromatic compounds preferably used which have at least one hydroxyl group are: phenol, o-cresol, m-cresol, 3-ethyl phenol, 2-tert-butyl phenol, guaiacol, guetol.
As regards the type of catalyst used, an at least difunctional acid can be used which corresponds to the following formula (II):
HOOCxe2x80x94R1xe2x80x94COOHxe2x80x83xe2x80x83(II)
in which formula (II), R1 represents a valency bond or an optionally substituted hydrocarbon radical containing 1 to 40 carbon atoms.
To be more exact, in formula (II), R1 symbolises a substituted or non-substituted hydrocarbon radical which can be a linear or branched, saturated or unsaturated acyclic aliphatic radical; a monocyclic or polycyclic, saturated, unsaturated, or aromatic carbocyclic radical; a monocyclic or polycyclic, saturated, unsaturated or aromatic heterocyclic radical.
The compounds with at least two carboxylic functions of general formula (II) in which R1 represents a valency bond or a divalent radical preferably having 1 to 15 carbon atoms are quite particularly suitable for implementation of the process according to the invention.
The compounds with at least two carboxylic functions of general formula (II) in which R1 represents a linear or branched, saturated or unsaturated aliphatic residue are particularly well suited for use of the process according to the invention.
To be more exact, R1 represents a linear or branched, acyclic aliphatic residue having preferably 1 to 12 carbon atoms, saturated or containing one or more unsaturations on the chain, generally 1 to 3 unsaturatiors which can be single or conjugated double bonds, or triple bonds.
The hydrocarbon chain can optionally be:
(1)xe2x80x94interrupted by one of the following groups called Y: 
in which formula R2 represents hydrogen or a linear or branched alkyl radical having 1 to 4 carbon atoms, preferably a methyl or ethyl radical, or a radical of xe2x80x94(CH2)pxe2x80x94COOH type in which p is a number between 1 and 5,
(2)xe2x80x94and/or bearing one of the following substituents:
xe2x80x94OH; xe2x80x94COOH; xe2x80x94CHO; xe2x80x94NO2; xe2x80x94CN; xe2x80x94NH2; xe2x80x94SH; xe2x80x94X; CF3 
xe2x80x94NHxe2x80x94[(CH2)pxe2x80x94COOH] or xe2x80x94Nxe2x80x94[(CH2)pxe2x80x94COOH]2 
with X representing a halogen atom, preferably a fluorine, chlorine or bromine atom, and p having the meaning given hereinabove.
The compounds with at least two carboxylic functions of general formula (II) in which R1 represents a monocylic or polycyclic hydrocarbon residue are also suitable for implementation of the process according to the invention.
R1 preferably represents an aromatic hydrocarbon residue, and, in particular, a benzene residue corresponding to the general formula (III): 
in which formula (III):
n is an integer from 0 to 4, preferably from 0 to 3,
R3 represents ones of the following groups or functions,
a hydrogen atom,
a linear or branched alkyl radical having from 1 to 4 carbon atoms,
a linear or branched alkoxy radical having from 1 to 4 carbon atoms,
a methylene or ethylene dioxy radical,
a xe2x80x94CHO group,
a phenyl or benzyl radical,
a halogen atom,
Even more preferably, the compounds of formula (II) are selected in which the R1 radical corresponds to formula (III) in which the R3 radicals, which are identical or different, are a hydrogen atom, a methyl radical, a methoxy radical, a xe2x80x94CHO group.
The compounds having at least two carboxylic functions can correspond to general formula (II) in which the R1 radical represents a polycyclic aromatic hydrocarbon divalent residue; the rings can form between themselves ortho condensed, ortho- and peri-condensed systems. More particularly, a naphthylenic residue can be mentioned; said rings being able to be substituted by 1 to 4 R3 radicals, preferably by 1 to 3, R3 having the meanings stated hereinabove for the substituents of the aromatic hydrocarbon residue of general formula (III).
In general formula (II) of the compounds with at least two carboxylic functions, R1 can also represent a carbocyclic residue which is saturated or which comprises 1 or 2 unsaturations in the ring, generally having from 3 to 7 carbon atoms, preferably 6 carbon atoms in the ring; said ring being able to be substituted by 1 to 5, preferably 1 to 3, R3 radicals, R3 having the meanings stated hereinabove for the substituents of the aromatic hydrocarbon residue of general formula (III).
As preferred examples of R1 radicals the cyclohexane-diyl radicals can be mentioned which are optionally substituted by linear or branched alkyl radicals having 1 to 4 carbon atoms.
The compounds with at least two carboxylic functions can also correspond to formula (II) in which R1 represents a divalent radical constituted by a chain formation of two to four residues as defined hereinabove, an aliphatic residue, an aromatic residue, or a cycloaliphatic residue. These can be connected together by a valency bond or by a function group which can be, in particular, a group selected from the groups called Y.
Some examples of R1 radicals are given hereinafter:
xe2x80x94CH2xe2x80x94C6h4xe2x80x94;
xe2x80x94CH2xe2x80x94CH2xe2x80x94C6H4xe2x80x94;
xe2x80x94CH2xe2x80x94Oxe2x80x94C6H4xe2x80x94;
xe2x80x94CH2xe2x80x94Oxe2x80x94C6H4xe2x80x94;
xe2x80x94CH2xe2x80x94Oxe2x80x94C6H4xe2x80x94CH2xe2x80x94;
xe2x80x94C6H4xe2x80x94C6H4xe2x80x94;
xe2x80x94C6H4xe2x80x94CH2C6H4xe2x80x94;
xe2x80x94C6H4xe2x80x94Oxe2x80x94C6H4xe2x80x94;
xe2x80x94CH2xe2x80x94C6H4xe2x80x94CH2xe2x80x94C6H4xe2x80x94CH2xe2x80x94
The following compounds with at least two carboxylic functions can be mentioned, quite particularly, by way of catalysts which are suitable for the present invention:
dicarboxylic aliphatic acids, such as:
oxalic acid
malonic acid
succinic acid
glutaric acid
adipic acid
2,4-dimethyl adipic acid
pimelic acid
suberic acid
azelaic acid
sebacic acid
dodecane dioic acid
fumaric acid
maleic acid
cycloalkanedicarboxylic acids, such as cyclohexane 1,4-dicarboxylic acid,
aromatic dicarboxylic acids, such as:
phthalic acid
isophthalic acid
terephthalic acid
phenylenediacetic acid
naphthalene 1,5-dicarboxylic acid
naphthalene 1,6-dicarboxylic acid
4,4xe2x80x2-diphenylcarboxylic acid
3,3xe2x80x2-diphenylcarboxylic acid
bis(4-hydroxycarbonyl)phenyl oxide
bis(3-hydroxycarbonyl)phenyl oxide
4,4xe2x80x2-dihydroxycarbonyl diphenylsulphone
3,3xe2x80x2-dihydroxycarbonyl diphenylsulphone
pyrimidine or imidazole dicarboxylic acids.
In the afore-mentioned list of dicarboxylic acids, the compounds preferably used are: oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, sebacic acid, phthalic acid, isophthalic acid, terephthalic acid.
Aminopolycarboxylic acids are also perfectly well suited for implementation of the process according to the invention. As examples of aminopolycarboxylic acids suitable for use in the process of the invention mention can be made of the following, inter alia:
ethylenediaminotetracetic acid (E.D.T.A.)
diethylenetriaminopentacetic acid (D.T.P.A.)
nitrilotriacetic acid (N.T.A.)
N-(2-hydroxyethylethylene diaminotriacetic acid (H.E.D.T.A.)
Of the afore-mentioned aminopolycarboxylic acids, ethylenediaminotetracetic acid is preferably selected.
According to the process of the invention, the reaction is carried out in the presence of an alkali metal hydroxide which can be sodium or potassium hydroxide.
For economic considerations, sodium hydroxide is preferably selected.
With regard to the concentrations and quantities of reagents to be used, the preferred conditions are defined hereinbelow.
In accordance with the process according to the invention a solution of glyoxylic acid is used. The concentration of said solution is not critical and can vary greatly, e.g. between 15 and 70% by weight. Preferably, commercial solutions are used, the concentration of which is approximately 50%.
According to the process of the invention, the glyoxylic acid is reacted on the excess of the hydroxylated aromatic compound of formula (I). The molar ratio between the hydroxylated aromatic compound of formula (I) and the glyoxylic acid varies between 1.5 and 4.0 and is preferably selected between 2.0 and 3.0.
The alkali metal hydroxide solution used has a concentration which is generally between 10 and 50% by weight. The concentration of the starting solution is not critical. However, as the concentration of the hydroxylated aromatic compound of formula (I) is advantageously low in the reaction medium, a dilute solution of alkali metal is used to carry out the dilution of the reaction medium.
The quantity of alkali metal hydroxide introduced into the reaction medium takes account of the quantity necessary to salify the hydroxyl function of the hydroxylated aromatic compound of formula (I) and of the quantity necessary to salify the carboxylic function of the glyoxylic acid.
If the hydroxylated aromatic compound of formula (I) has salifiable functions other than the hydroxyl group, the quantity of alkali metal hydroxide necessary to salify all the salifiable functions which can be hydroxyl groups and/or COOH carboxylic functions is therefore introduced.
Generally, the quantity of alkali metal hydroxide can vary greatly and be equal to, or approximately equal to, the stoichiometry, or in excess. Generally, the quantity of alkali metal hydroxide varies between 80 and 120% of the stoichiometric quantity.
The concentration of the hydroxylated aromatic compound of formula (I) is preferably between 0.5 and 1.5 moles/liter, and, more particularly, in the region of 1 mole/liter. With regard to the quantity of catalyst used, this is determined in such a way that the molar ratio between the catalyst and the hydroxylated aromatic compound of formula (I) is between 0.005 and 0.025, and preferably between 0.01 and 0.02.
The quantity of catalyst used, as expressed by the ratio between the number of moles of catalyst and the number of moles of glyoxylic acid is advantageously selected to be between 0.5 and 2.5%, preferably between 1 and 2%.
The preferred catalyst is oxalic acid.
The commercial solutions of glyoxalic acid can contain very low quantities of oxalic acid. The oxalic acid of the reaction can therefore be provided, in part, by the starting solution. In this case, it will be necessary to complete the quantity of oxalic acid by the addition of oxalic acid or of any other dicarboxylic acid in order that the afore-mentioned ratios are observed.
According to a preferred embodiment of the invention, a solution of glyoxylic acid is advantageously used containing between 0.6 and 3%, preferably between 1.2 and 2.6%, by weight of oxalic acid, expressed in relation to the weight of glyoxylic acid.
The reaction temperature is advantageously selected between 20xc2x0 C. and 60xc2x0 C., and preferably between 30xc2x0 C. and 40xc2x0 C.
The process according to the invention is carried out at atmospheric pressure, but under a controlled inert gas atmosphere, preferably nitrogen or rare gases, in particular nitrogen.
A preferred practical embodiment of the invention will be given hereinafter.
The solution of glyoxylic acid and catalyst, and, in parallel, the solution of alkali metal hydroxide employed in a quantity necessary to salify the COOH function are introduced into a reaction medium containing the hydroxylated aromatic compound of formula (I), water and the alkali metal hydroxide in a quantity necessary to salify the hydroxyl group and other possible salifiable functions of the compound of formula (I).
The reaction mediun is kept under agitation and at the temperature selected within the aforementioned range for a variable period ranging from 1 to 10 hours.
Another variant of the execution of the invention consists in adding the reaction catalyst not to the aqueous solution of glyoxylic acid but simultaneously with the hydroxylated aromatic compound of formula (I).
At the end of the reaction, the optionally substituted p-hydroxymandelic acid obtained is separated in salified form using conventional separation techniques, in particular crystallisation.
The process according to the invention is quite particularly well suited when an aqueous solution of glyoxylic acid is used containing monofunctional acids, such as formic and glycolic acid, and, in particular, when acetic acid is present in a concentration which is variable between 0.1 and 3%.
The process according to the invention results in the production of optionally substituted p-hydroxymandelic compounds which can be represented by the following formula (I): 
in which formula (IV) R and x have the meaning given in formula (I).
These products are particularly worthwhile since they are intermediate products, which, inter alia, allow hydroxyarylacetic acids to be obtained by reduction and hydroxyarylglyoxylic (=hydroxyaryl xcex1-oxo acetic) acids or hydroxyaromatic aldehydes to be obtained by oxidation.
A preferred use of the invention is the preparation of hydroxyaromatic aldehydes by oxidation of the compounds of formula (IV) obtained according to the invention.
The oxidation of the compounds of formula (IV) can be carried out according to the techniques described in writings. Thus, reference can be made to P. HEBERT [Bull. Soc. Chim. France, 27, p. 45-55 (1920)] and to NAGAI SHIGEKI et al [JP-A 76/128934]. The oxidation is generally carried out using oxygen or air under pressure, in the presence of an appropriate catalyst, such as derivatives of chromium, cobalt, copper, vanadium or osmium, for example.
Therefore, the invention allows easy access to 4-hydroxy benzaldehyde and to vanillin and its analogues, e.g. 3-ethyl, 3-isopropyl vanillin, by oxidation respectively of p-hydroxymandelic acid and of 3-methoxy p-hydroxymandelic acids, and 3-ethoxy p-hydroxy-mandelic or 3-isopropoxy p-hydroxymandelic acids.
The following examples illustrate the invention, without however limiting it.
In the examples, the percentages stated are expressed by weight.
The abbreviations mentioned in the examples have the following meanings: